Renal Control of Body Fluid Volume and Circulatory Dynamics

该计划项目的一个主要主题是肾体液反馈控制系统， 肾脏在体液量和动脉压的长期调节中发挥着主导作用。一 迄今为止，在所有形式的高血压检查中发现了一种常见的肾脏异常，包括遗传性 而实验模型和人类原发性高血压是一种高血压性移液性压力钠尿排泄 关系项目II“的一个主要目标是研究内皮素，一氧化氮， 氧化应激和新的抗血管生成因子介导肾压尿钠排泄减少 与内皮功能障碍相关的特定形式的高血压先兆子痫（PE）。高血压 与PE相关的疾病在妊娠期间发生，并在分娩后缓解，涉及胎盘作为中枢 疾病的罪魁祸首。PE的起始事件被假定为涉及胎盘灌注减少， 广泛的母体血管内皮功能障碍的机制仍有待阐明。最近 对先兆子痫妇女的研究表明， 可溶性fms样酪氨酸激酶-1（sFlt-1），一种天然存在的血管内皮生长因子拮抗剂 （VEGF）和胎盘生长因子（PlGF）。先兆子痫期间sFlt-1的增加与 血浆VEGF和PIGF。此外，腺病毒介导的sFlt-1给药至妊娠大鼠以模拟 在先兆子痫妇女中观察到的血浆浓度，减少游离VEGF和PIGF，并产生 高血压和蛋白尿。虽然这些新的发现暗示sFlt-1在糖尿病的发病机制中起作用， 尽管在先兆子痫期间存在高血压，但仍不清楚的是导致过量sFlt的具体机制， 1生产和机制，其中sFlt-1增加血压在怀孕期间。基于我们 初步数据，我们建议测试中心假设，降低子宫灌注压（RUPP）， 妊娠大鼠通过ANGII和TNF-α依赖性机制增加胎盘sFlt-1。的增加 sFlt-1的血浆浓度降低，反过来导致VEGF和PlGF的血浆浓度降低。在 此外，我们提出，在妊娠期间慢性sFlt-1过量损害肾功能，并增加总的 通过降低血浆中游离VEGF和PIGF的浓度， 导致内皮细胞功能障碍，表现为ET-1、ROS的产生增加和NO的减少。 为了检验这一假设，将在一个实验室中检查动脉压、肾脏、激素和内皮因素。 通过长期RUPP产生的清醒的、慢性仪器化的PE大鼠模型。除了RUPP 模型，PE的sFlt-1模型将用于确定sFlt-1与ET-1、ROS和NO之间的相互作用 生产，而体外胎盘外植体模型将用于检查直接相互作用 缺氧和胎盘sFlt-1、ANGII和TNF-α产生。

A major theme of this Program Project has been the renal-body fluid feedback control system in which the kidneys play a dominant role in the long-term regulation of body fluid volumes and arterial pressure. A common renal abnormality that has been found in all forms of hypertension examined to date, including genetic and experimental models and human essential hypertension is a hypertensive shift in the pressure natriuresis relationship. A major objective of Project II "is to examine the interactions between endothelin, nitric oxide, oxidative stress and novel anti-angiogenic factors in mediating the reduction in renal-pressure natriuresis in a specific form of hypertension associated with endothelial dysfunctionpreeclampsia (PE). Hypertension associated with PE develops during pregnancy and remits after parturition implicating the placenta as a central culprit in the disease. The initiating event in PE is postulated to involve reduced placental perfusion that leads to widespread maternal vascular endothelial dysfunction by mechanisms that remain to be elucidated. Recent studies in preeclamptic women have demonstrated increased placental and circulating concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), a naturally occurring antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). Increased sFlt-1 during preeclampsia is associated with decreased free plasma VEGF and PIGF. Moreover, adenovirus mediated administration of sFlt-1 to pregnant rats to mimic plasma concentrations observed in preeclamptic women, decreases free VEGF and PIGF and produces hypertension and proteinuria. Although these novel findings implicate sFlt-1 in the pathogenesis of hypertension during preeclampsia, what remains unclear are the specific mechanisms that lead to excess sFlt- 1 production and the mechanisms whereby sFlt-1 increases blood pressure during pregnancy. Based on our preliminary data, we propose to test the central hypothesis that reduced uterine perfusion pressure (RUPP) in the pregnant rat increases placental sFlt-1 via ANGII and TNF-ct dependent mechanisms. The increase in plasma concentration of sFlt-1, in turn results in decreased plasma concentrations of VEGF and PIGF. In addition, we propose that chronic sFlt-1 excess during pregnancy impairs renal function and increases total peripheral resistance and blood pressure by decreasing plasma concentrations of free VEGF and PIGF which contribute to endothelial cell dysfunction marked by enhanced production of ET-1, ROS and decreased NO. To test this hypothesis arterial pressure, renal, hormonal, and endothelial factors will be examined in a conscious, chronically instrumented rat model of PE produced by long-term RUPP. In addition to the RUPP model, a sFlt-1 model of PE will be used to determine the interaction between sFlt-1 and ET-1, ROS, and NO production while an in vitro placental explant model will be used to examine the direct interaction between hypoxia and placental sFlt-1, ANGII, and TNF-a production.